PAD is a condition in which the arteries are narrowed outside the heart specifically lower extremities arteries, reducing blood flow in the peripheral artery [1, 2]. Most PAD is asymptomatic, but if it continues untreated, the muscles will be starved of oxygen, and claudication will appear [2]. Recently, trimetazidine, an anti-ischemic agent, has been introduced for patients with PAD as the clinician might consider its therapeutic effect on skeletal muscle could resemble its well-known beneficial effect in the myocardial muscle of patients with stable coronary artery disease. Regarding the authors' knowledge, this current meta-analysis and systematic review was the first research addressing this issue [13].

Trimetazidine is a cytoprotective medication that, through several mechanisms of action, normalizes metabolic abnormalities in low-flow ischemia. The most well-known way trimetazidine works is by preventing the oxidation of free fatty acids (FFA) [13]. Trimetazidine accelerates the metabolism of glucose by specifically blocking long-chain 3-ketoacyl coenzyme A thiolase (LC 3-KAT), the FFA-oxidation pathway’s last enzyme [13, 14]. Additionally, trimetazidine improves the activity of the enzyme pyruvate dehydrogenase, which reduces the amount of oxygen used during the synthesis of adenosine 5′-triphosphate (ATP), creating hydrogen ions, the amount of intracellular acidosis, and the reduced accumulation of calcium ions [13]. Another aspect of the action of trimetazidine mechanism that may be crucial for people with cardiovascular disease, including those who have chronic heart failure (CHF), is its direct suppression of cardiac fibrosis through enhancing connective tissue growth factor (CTGF) [13].

ABI is a simple, feasible, non-invasive, and affordable test tool for diagnosing PAD [15]. According to AHA, PAD is diagnosed when ABI is ≤ 0.9 [16]. As ABI reflects the degree of arterial occlusion due to lumen narrowing, it could be used as one of the therapeutic parameters in PAD [17]. Our included study individually showed that ABI improvement between trimetazidine-receiving and control at the end of the study did not look markedly different. It is confirmed by our pooled finding, which also found insignificant differences in SMD between groups. This finding could happen as trimetazidine did not work on the pathogenesis and pathophysiology of plaque formation. However, this conclusion should be considered an interim finding in the setting of the scarcity of evidence as the therapy evaluation was considered short (3 and 6 months).

Progressive deterioration of the arterial lesion causes claudication and reduces walking capacity. Clinical evidence of a decline in walking ability at POT and MWD supports this theory. This test is often done until the pain becomes more severe at a steady pace and flat surface. According to the Fontaine or Rutherford classification, MWD is the major index for determining the severity of PAD. [18]

Our pooled finding suggested that the MWD improvement was notably higher in trimetazidine than in control groups. This finding is in line with the backgrounding theories on trimetazidine administration in patients with intermittent claudication. Reduced blood flow and oxygenation distal to the lumen narrowing promotes cellular anaerobic metabolism, leading to the lactic acid build-up in the interstitium. Growth factors and inflammatory cytokines release are also increased as the muscle tissue is hypoxic. The build-up of anaerobic metabolites and endogenous substances led to various receptors and channels of upregulation involved in sensory input transmission and perceived as pain stimuli by the central nervous system [11]. According to a prior study, the maximal rate of adenosine triphosphate (ATP) synthesis in skeletal muscle mitochondria was positively correlated with the activity level of the muscle during treadmill activity, and the walking distance of those with PAD was inversely related to their adenosine diphosphate concentration (ADP) [19]. Trimetazidine works by optimizing aerobic metabolism in skeletal muscle and reducing the amount of oxygen needed to produce ATP [13]. This could lead to less and delay of lactic acid, proton, proinflammatory cytokines, and growth factors accumulation that could stimulate pain in peripheral nerve ending [11]. The patients eventually could perform longer walking distances as the pain improves. This possible explanation could also explain better MWT and POT in trimetazidine receiving compared to the control group, as reported by Chu et al. [20]

However, this present review possesses several limitations. The number of pooled data was considerably low (n = 378 patients). One of the included studies did not undergo randomization, and another might have a selection of reported result issues. Moreover, there was a study with unequal baseline characteristics rendering carefulness in responding to this research findings. Also, we could not carry out a subgroup analysis because there were no data on PAD patients with or without history of coronary artery disease in any of the included studies. However, as far as our knowledge, this study is the first systematic review addressing the trimetazidine administration in PAD and could contribute to providing a summary of recent evidence and be a stepping stone for further exploration to enrich data in this field.